Mild traumatic brain injury (mTBI), alternatively referred to as concussion, is the most common neurological injury and affects over 1.5 million children and adults each year in the United States alone, and hundreds of thousands of military personnel worldwide. mTBI is of increasing concern for participants in contact sports. For athletes and other mTBI sufferers, post-concussion symptoms commonly resolve within hours or days, but for a small proportion of cases brain dysfunction and disability can persist, sometimes for a year or longer. For athletes, challenges remain to make neurobiologic ally-informed decisions on suitability for return to play and vulnerability to repetitive injuries.
mTBI is typically undetectable with computerized tomography (CT), yet can elicit long-term and clinically significant brain dysfunction in approximately 15-30% of cases. Histopathological and biomechanical findings in experimental animal models and human cases that have come to autopsy suggest that the main underlying structural correlate for long-term functional impairment after mTBI is diffuse axonal injury (DAI), resulting from head rotational acceleration at the moment of injury. Developing neuroradiological methods such as diffusion tensor imaging (DTI) have shown promise for the detection of white matter structural abnormalities after mTBI, but collectively these studies have yielded inconsistent results. Consequently, new approaches are urgently needed for the rapid identification of mTBI patients at risk of developing brain damage and persistent disability.
Blood-based biomarkers for brain damage have long been evaluated as potential prognostic measures in mTBI, but none has emerged thus far as a means of identifying at an early and potentially treatable stage those cases of mTBI with evolving brain damage leading to long-term dysfunction. For example, a number of proteins expressed predominantly in the to nervous system become detectable in the blood during the acute post-injury period in some mTBI cases, including the astrocyte-enriched proteins S100β and glial fibrillary acidic protein (GFAP), along with the neuron-enriched neuron-specific enolase (NSE), ubiquitin C-terminal hydrolase L1 (UCH-L1), αII-spectrin C-terminal fragments and a proteolytic fragment of tau. Unfortunately, none of these markers has a prognostic relationship with patient outcomes for mTBI with negative head CT findings.
Blood levels of these markers for brain damage are reportedly elevated following injuries categorized as mild based on clinical examinations using the Glasgow Coma Scale. However, these studies have focused predominantly on TBI cases that also show head CT abnormalities, and based on the positive CT findings these patients would be diagnosed with moderate TBI or “complicated” mTBI at most centers. Positive CT findings are known to be associated with poorer long-term outcomes after TBI, and the presence of intracranial hemorrhages suggests that the blood-brain barrier exhibits at least transient permeability that could impact blood-based biomarker measures. Unfortunately, for the much more common instances of CT-negative mTBI, which includes the vast majority of sports-related concussions, blood-based markers for brain injury have yet to be discovered that are strong predictors of structural damage and long-term functional outcome.
Therefore, there is a need in the art for neurodegeneration biomarkers released from degenerating neurons that are indicative of CT-negative mTBI. As well, there is a need in the art for neurodegneration biomarkers released from degenerating neurons that are indicative of mTBI, when evaluation by CT-scan is not available or has not been performed. This need is especially acute for subjects participating in sport activities. The present invention addresses these needs by providing methods for using calpain-cleaved αII-spectrin N-terminal fragment (SNTF) as a mechanism-based marker for the diffuse axonal injury that underlies brain functional impairment after mTBI/concussion.